RATIONALE: Blood vessel growth and patterning have been shown to be regulated by nerve-derived signals. Desert hedgehog (Dhh), one of the Hedgehog family members, is expressed by Schwann cells of peripheral nerves. OBJECTIVE: The purpose of this study was to investigate the contribution of Dhh to angiogenesis in the setting of ischemia. METHODS AND RESULTS: We induced hindlimb ischemia in wild-type and Dhh(-/-) mice. First, we found that limb perfusion is significantly impaired in the absence of Dhh. This effect is associated with a significant decrease in capillary and artery density in Dhh(-/-). By using mice in which the Hedgehog signaling pathway effector Smoothened was specifically invalidated in endothelial cells, we demonstrated that Dhh does not promote angiogenesis by a direct activation of endothelial cells. On the contrary, we found that Dhh promotes peripheral nerve survival in the ischemic muscle and, by doing so, maintains the pool of nerve-derived proangiogenic factors. Consistently, we found that denervation of the leg, immediately after the onset of ischemia, severely impairs ischemia-induced angiogenesis and decreases expression of vascular endothelial growth factor A, angiopoietin 1, and neurotrophin 3 in the ischemic muscle. CONCLUSIONS: This study demonstrates the crucial roles of nerves and factors regulating nerve physiology in the setting of ischemia-induced angiogenesis.
RATIONALE: Blood vessel growth and patterning have been shown to be regulated by nerve-derived signals. Desert hedgehog (Dhh), one of the Hedgehog family members, is expressed by Schwann cells of peripheral nerves. OBJECTIVE: The purpose of this study was to investigate the contribution of Dhh to angiogenesis in the setting of ischemia. METHODS AND RESULTS: We induced hindlimb ischemia in wild-type and Dhh(-/-) mice. First, we found that limb perfusion is significantly impaired in the absence of Dhh. This effect is associated with a significant decrease in capillary and artery density in Dhh(-/-). By using mice in which the Hedgehog signaling pathway effector Smoothened was specifically invalidated in endothelial cells, we demonstrated that Dhh does not promote angiogenesis by a direct activation of endothelial cells. On the contrary, we found that Dhh promotes peripheral nerve survival in the ischemic muscle and, by doing so, maintains the pool of nerve-derived proangiogenic factors. Consistently, we found that denervation of the leg, immediately after the onset of ischemia, severely impairs ischemia-induced angiogenesis and decreases expression of vascular endothelial growth factor A, angiopoietin 1, and neurotrophin 3 in the ischemic muscle. CONCLUSIONS: This study demonstrates the crucial roles of nerves and factors regulating nerve physiology in the setting of ischemia-induced angiogenesis.
Authors: Cameron A Schmidt; Adam J Amorese; Terence E Ryan; Emma J Goldberg; Michael D Tarpey; Thomas D Green; Reema R Karnekar; Dean J Yamaguchi; Espen E Spangenburg; Joseph M McClung Journal: Am J Pathol Date: 2018-02-16 Impact factor: 4.307
Authors: Ciaran J Mooney; Roya Hakimjavadi; Emma Fitzpatrick; Eimear Kennedy; Dermot Walls; David Morrow; Eileen M Redmond; Paul A Cahill Journal: Stem Cells Int Date: 2015-05-06 Impact factor: 5.443
Authors: Joseph M McClung; Jessica L Reinardy; Sarah B Mueller; Timothy J McCord; Christopher D Kontos; David A Brown; Sabah N A Hussain; Cameron A Schmidt; Terence E Ryan; Tom D Green Journal: Front Physiol Date: 2015-05-19 Impact factor: 4.566
Authors: Lauren Sweet; Yunqing Kang; Christopher Czisch; Lukasz Witek; Yang Shi; Jim Smay; Giles W Plant; Yunzhi Yang Journal: PLoS One Date: 2015-10-07 Impact factor: 3.240